Transmissible spongiform encephalopathies (TSEs) attracted increasedattention in the mid-1980s because of the emergence among UK cattle ofbovine spongiform encephalopathy (BSE), which has been shown to betransmitted to humans, causing a variant form of Creutzfeldt-Jakobdisease (vCJD). The BSE outbreak has been reported in 19 Europeancountries, Israel, and Japan, and human cases have so far beenidentified in four European countries, and more recently in a Canadianresident and a US resident who each lived in Britain during the BSEoutbreak. To monitor the occurrence of emerging forms of CJD, such asvCJD, in the United States, the Centers for Disease Control andPrevention has been conducting surveillance for human TSEs throughseveral mechanisms, including the establishment of the National PrionDisease Pathology Surveillance Center. Physicians are encouraged tomaintain a high index of suspicion for vCJD and use the free services ofthe pathology center to assess the neuropathology of clinicallydiagnosed and suspected cases of CJD or other TSEs.

http://www.neurology.org/cgi/content/abstract/60/2/176

# Monitoring the occurrence of emerging forms of Creutzfeldt-Jakobdisease in the United States [FULL TEXT] - TSS 2/22/03 (0)

http://www.vegsource.com/talk/madcow/messages/9912538.html

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RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakobdisease in the United States

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakobdisease in the United States

Terry S. Singeltary Neurology Online, 27 Jan 2003 [Full text]

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakobdisease in the United States 26 March 2003Next Post-Publication Peer Review Top Terry S. Singeltary,retired (medically)CJD WATCH

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I lost my mother to hvCJD (Heidenhain Variant CJD). I would like tocomment on the CDC's attempts to monitor the occurrence of emergingforms of CJD. Asante, Collinge et al [1] have reported that BSEtransmission to the 129-methionine genotype can lead to an alternatephenotype that is indistinguishable from type 2 PrPSc, the commonestsporadic CJD. However, CJD and all human TSEs are not reportablenationally. CJD and all human TSEs must be made reportable in everystate and internationally. I hope that the CDC does not continue toexpect us to still believe that the 85%+ of all CJD cases which aresporadic are all spontaneous, without route/source. We have many TSEs inthe USA in both animal and man. CWD in deer/elk is spreading rapidly andCWD does transmit to mink, ferret, cattle, and squirrel monkey byintracerebral inoculation. With the known incubation periods in otherTSEs, oral transmission studies of CWD may take much longer. Everyvictim/family of CJD/TSEs should be asked about route and source of thisagent. To prolong this will only spread the agent and needlessly exposeothers. In light of the findings of Asante and Collinge et al, thereshould be drastic measures to safeguard the medical and surgical arenafrom sporadic CJDs and all human TSEs. I only ponder how many sporadicCJDs in the USA are type 2 PrPSc?

Mr. Singletary raises several issues related to current Creutzfeldt-Jakob disease (CJD) surveillance activities. Although CJD is not anotifiable disease in most states, its unique characteristics,particularly its invariably fatal outcome within usually a year ofonset, make routine mortality surveillance a useful surrogate forongoing CJD surveillance.1 In addition, because CJD is least accuratelydiagnosed early in the course of illness, notifiable-diseasesurveillance could be less accurate than, if not duplicative of, currentmortality surveillance.1 However, in states where making CJD officiallynotifiable would meaningfully facilitate the collection of data tomonitor for variant CJD (vCJD) or other emerging prion diseases, CDCencourages the designation of CJD as a notifiable disease.1 Moreover,CDC encourages physicians to report any diagnosed or suspected CJD casesthat may be of special public health importance (e.g., vCJD, iatrogenicCJD, unusual CJD clusters). As noted in our article, strong evidence islacking for a causal link between chronic wasting disease (CWD) of deerand elk and human disease,2 but only limited data seeking such evidenceexist. Overall, the previously published case-control studies that haveevaluated environmental sources of infection for sporadic CJD have notconsistently identified strong evidence for a common risk factor.3However, the power of a case-control study to detect a rare cause of CJDis limited, particularly given the relatively small number of subjectsgenerally involved and its long incubation period, which may last fordecades. Because only a very small proportion of the US population hasbeen exposed to CWD, a targeted surveillance and investigation ofunusual cases or case clusters of prion diseases among persons atincreased risk of exposure to CWD is a more efficient approach todetecting the possible transmission of CWD to humans. In collaborationwith appropriate local and state health departments and the NationalPrion Disease Pathology Surveillance Center, CDC is facilitating orconducting such surveillance and case- investigations, including relatedlaboratory studies to characterize CJD and CWD prions. Mr. Singletaryalso expresses concern over a recent publication by Asante andcolleagues indicating the possibility that some sporadic CJD cases maybe attributable to bovine spongiform encephalopathy (BSE).4 The authorsreported that transgenic mice expressing human prion protein homozygousfor methionine at codon 129, when inoculated with BSE prions, developeda molecular phenotype consistent with a subtype of sporadic CJD.Although the authors implied that BSE might cause a sporadic CJD-likeillness among persons homozygous for methionine, the results of theirresearch with mice do not necessarily directly apply to the transmissionof BSE to humans. If BSE causes a sporadic CJD-like illness in humans,an increase in sporadic CJD cases would be expected to first occur inthe United Kingdom, where the vast majority of vCJD cases have beenreported. In the United Kingdom during 1997 through 2002, however, theoverall average annual mortality rate for sporadic CJD was not elevated;it was about 1 case per million population per year. In addition, duringthis most recent 6-year period following the first published descriptionof vCJD in 1996, there was no increasing trend in the reported annualnumber of UK sporadic CJD deaths.3, 5 Furthermore, surveillance in theUK has shown no increase in the proportion of sporadic CJD cases thatare homozygous for methionine (Will RG, National CJD Surveillance Unit,United Kingdom, 2003; personal communication).

SUBMITTED 3/26/03Here is what your Post-Publication Peer Review will look like online:Re: RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakobdisease in the United StatesTerry S. Singeltary,disabledCJD WATCH,NA

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Greetings again Neurology,

i must respectfully disagree with Ryan Maddox, MPH, et al. looks likesporadic CJDs are increasing to me, but some will just claim bettersurveillance i suppose. odd how the USA can claim better surveillancewhen CJD is not reportable in most states and the elderly demented donot get autopsied in most cases. most doctors and medical personnel ihave dealt with knew absolutely nothing about CJD, much lesshuman/animal TSEs. so how would one know? also, i must say, this statement;

>>>In addition, because CJD is least accurately diagnosed early in thecourse of illness, notifiable-disease surveillance could be lessaccurate than, if not duplicative of, current mortality surveillance.<<<

this is very disturbing to me, if most elderly demented (either fast orslow Alzheimer's and other related demented disease's are not autopsied,and they die from disease's brought on by dementia in the terminallyill, and this is what is put on the death certificate, then how wouldmortality surveillance pick up these false diagnosis of cause of death?several studies have shown a substantial number of misdiagnosed cases ofTSEs;

Diagnosis of dementia: Clinicopathologic correlations

Francois Boller, MD, PhD; Oscar L. Lopez, MD; and John Moossy, MD

Article abstract--Based on 54 demented patients consecutively autopsiedat the University of Pittsburgh, we studied the accuracy of cliniciansin predicting the pathologic diagnosis. Thirty-nine patients (72.2%) hadAlzheimer's disease, while 15 (27.7%) had other CNS diseases (fourmulti-infarct dementia; three Creutzfeldt-Jakob disease; two thalamicand subcortical gliosis; three Parkinson's disease; one progressivesupranuclear palsy; one Huntington's disease; and one unclassified). Twoneurologists independently reviewed the clinical records of each patientwithout knowledge of the patient's identity or clinical or pathologicdiagnoses; each clinician reached a clinical diagnosis based on criteriaderived from those of the NINCDS/ADRDA. In 34 (63 %) cases bothclinicians were correct, in nine (17%) one was correct, and in 11 (20%)neither was correct. These results show that in patients with a clinicaldiagnosis of dementia, the etiology cannot be accurately predictedduring life.

· To identify those patients most likely to benefit from a cerebralbiopsy to diagnose dementia, we reviewed a series of 14 unselectedbiopsies performed during a 9-year period (1980 through 1989) at DukeUniversity Medical Center, Durham, NC. Pathognomonic features allowed adefinitive diagnosis in seven specimens. Nondiagnostic abnormalities butnot diagnostic neuropathologic changes were seen in five additionalspecimens, and two specimens were normal. Creutzfeldt-Jakob disease wasthe most frequent diagnosis. One patient each was diagnosed as havingAlzheimer's disease, diffuse Lewy body disease, adult-onset Niemann-Pickdisease, and anaplastic astrocytoma. We conclude that a substantialproportion of patients presenting clinically with atypical dementia arelikely to receive a definitive diagnosis from a cerebral biopsy.However, in those with coexisting hemiparesis, chorea, athetosis, orlower motor neuron signs, cerebral biopsies are less likely to bediagnostic.

One of our papers (in Alzheimer's Disease Related Disord. 3:100-109,1989) in text cites 6 of 46 (13%) of clinical AD as CJD. There may be alater paper from another lab showing the same higher than expectedincidence but I can't put my hands on it right now. We also have a lotof papers from 1985 on stating that there are likely many silent(non-clinical) CJD infections, i.e. much greater than the "tip of theiceberg" of long standing end-stage cases with clinical symptoms. Hopethis helps.

best wishes for the new year laura manuelidis

BESIDES the increase in Switzerland, and despite the fact the U.K. didincrease from 1993 to 2002 from 37 to 63 cases of sporadic CJD, look atFrance, Germany, Italy and their increase of sporadic CJDs;

http://www.eurocjd.ed.ac.uk/sporadic.htm

The number of people dying from sporadic Creutzfeldt-Jakob disease (CJD)has risen sharply in Switzerland. The finding is raising fears that 'madcow disease' could have spread to humans in another form1.

http://www.nature.com/nsu/020708/020708-18.html

Nature 420, 450 (2002); doi:10.1038/420450a

Prion data suggest BSE link to sporadic CJD

DECLAN BUTLER

Predicting the number of cases of Creutzfeldt–Jakob disease (CJD) inpeople as a result of transmission of bovine spongiform encephalopathy(BSE) has just got more difficult.

Whereas it was thought that BSE only caused a new form of the diseasecalled variant CJD (vCJD), a study in mice from a team led by JohnCollinge at University College London suggests that it may also cause adisease indistinguishable from the commonest form of classical, or'sporadic', CJD (E. A. Asante et al. EMBO J. 21, 6358–6366; 2002). Ifthe group's mouse model is relevant to the human disease, the resultsalso suggest that the true extent of infection may be difficult toassess because of the large number of asymptomatic carriers.

The latest work uses mice engineered to carry the human gene for acell-membrane protein called PrP. Prion diseases occur when PrP isconverted to the abnormal 'prion' form, PrPSc. Collinge has developed atest, based on a standard western blot for analysing proteins, to studyPrPSc extracted from the brain. This previously showed disease caused byBSE or vCJD to give a characteristic molecular signature that isdistinct from sporadic CJD (J. Collinge, K. C. L. Sidle, J. Meads, J.Ironside and A. F. Hill Nature 383, 685–690; 1996).

In their latest experiments, Collinge and his team injected materialfrom the brains of cows with BSE or people with vCJD directly into thebrains of two strains of mice with a human PrP genotype known as 129MM.Almost 40% of the British population has this genotype. In one mousestrain, those that became infected showed the usual BSE pattern in thewestern blot. But in the other, Collinge's team tested 11 mice infectedwith BSE material using the western blot. Ten of them showed a patternconsistent with sporadic CJD.

The number of cases of sporadic CJD have been rising in Britain sincethe 1970s, and this had been attributed to better monitoring for thecondition. But in July, researchers led by Adriano Aguzzi of theUniversity Hospital Zurich reported a sudden increase in sporadic CJDfigures in Switzerland in 2001, and suggested that infection with BSEmight be to blame (see Nature 418, 266; 2002). Collinge's new dataprovide worrying molecular evidence that BSE might be to blame for therise in sporadic CJD.

In previous experiments, Collinge had injected BSE and vCJD materialinto mice with another human PrP genotype, known as 129VV. The new dataare thought to be more relevant to the transmission of BSE because allof the known human victims of vCJD have the 129MM genotype. Anotherworrying finding is that the 129MM mice seem to be more susceptible todeveloping a subclinical infection, with no obvious symptoms.

If a large pool of the British population is carrying a subclinical BSEinfection, this would have serious consequences for the potentialtransmission of the disease, for instance through contaminated surgicalinstruments. And although laboratory mice are short-lived, infectedhumans might go on to develop the disease later in life.

The UK Department of Health, which has been briefed by Collinge on hisfindings, says that it will ask its Spongiform Encephalopathy AdvisoryCommittee to consider the results closely at its next meeting inFebruary. Collinge says that an urgent nationwide screening of tonsilmaterial is needed to get a better estimate of the level of infection inthe population.

New findings from Professor John Collinge and his MRC Prion Unit teamhave increased our understanding of human prion diseases, for exampleCreutzfeldt-Jacob disease (CJD) which destroys the brain. Their workalso raises new research questions about susceptibility to exposure tothe infective agent that causes bovine spongiform encephalopathy (BSE),a similar brain disease that affects cows. The research is published inthe 28 November 2002 edition of the European Molecular BiologyOrganisation journal.

In order to study human susceptibility to BSE and the “species barrier”between cattle and humans, Professor Collinge’s team has developed micewhich have the human form of prion protein – the infectious protein, orprion, commonly believed to cause spongiform encephalopathies. The miceshow remarkably similar damage to that seen in people, indicating thatthese mice are a good model of the human disease. This means we can seehow prions from BSE and human new variant CJD (vCJD) – which is believedto be caused by BSE prion infection – act on the mice to mimic humanpatterns of the disease.

The experiments confirmed earlier findings that the BSE and vCJD prionsare closely similar. However, the scientists were surprised to see thatwhile some of the mice developed a disease pattern closely similar tohuman vCJD, others produced a pattern like a form of sporadic(classical) CJD. “Sporadic CJD” simply refers to a form of CJD with noknown cause (such as genetic mutation or accidental exposure to prions).It has always been possible that it may have multiple causes. These datasuggest that some cases of apparently sporadic CJD in the UK andelsewhere where people have been exposed to BSE prions may in fact becaused by BSE.

Professor John Collinge said “We are not saying that all or even mostcases of sporadic CJD are as a result of BSE exposure, but some morerecent cases may be – the incidence of sporadic CJD has shown an upwardtrend in the UK over the last decade. While most of this apparentincrease may be because doctors are now more aware of CJD and better atdiagnosing it, serious consideration should be given to a proportion ofthis rise being BSE-related. Switzerland, which has had a substantialBSE epidemic, has noted a sharp recent increase in sporadic CJD.

While few of the mice inoculated with BSE or vCJD prions showed clinicalsigns of disease, which might have suggested a good species barrier,closer examination revealed that many of the mice were in fact infected.This finding of a “sub-clinical” form of prion disease has beenrecognised before by this research group and now also seems relevant toBSE infection.

Further work in the paper argues that it is the genetic makeup of themice which determines whether BSE infection makes them produce the type4 prion strain (as seen in variant CJD in humans) or the type 2 strain(as seen in sporadic CJD in humans).

>>>Because only a very small proportion of the US population has beenexposed to CWD, a targeted surveillance and investigation of unusualcases or case clusters of prion diseases among persons at increased riskof exposure to CWD is a more efficient approach to detecting thepossible transmission of CWD to humans<<<

CWD is not the only TSE in the USA. we have Scrapie in sheep/goats, TMEin mink and the fact USA BSE/TSE surveillance in USA cattle to date hasbeen lacking, to say the least (re-recent reports from GAO). the cattleindustry has flagrantly violated the voluntary ruminant-to-ruminantpartial feed ban of 8/4/97 up and through 2002. all these TSEs being fedto different species of animals over the decades in the USA, subclinical TSEs, 2nd and 3rd passage of TSEs? we must not forget that;

IN CONFIDENCE Pathology Report:

HOUND SURVEY-REFERAL OF UNRESOLVED CASES

snip...

AS implied in the Inset 25 we must not _ASSUME_ that transmission of BSEto other species will invariably present pathology typical of ascrapie-like disease.

snip...

G A H WELLS 4 January 1991

http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf

ROUND TABLE ON BSE -- WASHINGTON -- 27-28 JUNE 1989

snip...

The summary does tend to give a particular slant to the epidemiology ofBSE which is not totally sound. It is a possibility that the agent ofBSE may be in the cattle population in a number of countries alreadyapart from the USA and that clinical cases are occurring on rareoccasions. It is also important to off the possibility of therelationship between BSE and certain low-temperature rendering systems.For that reason a number of other countries apart from the USA andFrance are at risk and, in particular, the Netherlands, Denmark, Germanyand Belgium. For these reasons it would be wise to move to aninternational ban on the feeding of ruminant protein to ruminants.

Clearly the summary also needs to refer to the incidence of BSE in theUK and not solely to Great Britain. No doubt this has been tidied up inyour comments on the summary conclusions. It is a pity that more of thecomments put forward by Dr. Kimberlin have not been included in thesummary since his views on page 13 are succinct and valuable...

snip...

http://www.bseinquiry.gov.uk/files/yb/1989/08/29003001.pdf

Is there a Scrapie-like disease in cattle ?

IN CONFIDENCE

R.F. MARSH

snip...

re-mink rancher 'Wisconsin' dead stock feeder using >95% downer or deaddairy and a few horses...

http://www.bseinquiry.gov.uk/files/yb/1987/06/10004001.pdf

As of March 11, CVM had received inspection reports covering inspections(both initial inspections and re-inspections) of 10,458 different firms.The majority of these inspections (around 80%) were conducted by Stateofficials under contract to FDA and the remainder by FDA officials.

Various segments of the feed industry had different levels of compliancewith this feed ban regulation. The results to date are reported hereboth by "segment of industry" and "in total".

i am not sure about 2003, they have ceased posting those warningletters. it seems i now have to go through the F.O.I.A. we have beenfeeding TSE infected ruminants to ruminants for decades. to only beconcerned with TSE to humans from only CWD in deer and elk in the USA,would be foolish in my opinion. besides, it would not take too many CWDinfected humans to spread the agent via the many other vectors fortransmission (medical/surgical arena, pharmaceuticals, supplements,)just to name a few potential routes.

with all due respect, with present data to date, further floundering onmaking all CJD/TSEs reportable in the USA, and further refusal to dealwith sporadic CJDs in the USA and around the Globe without CJDquestionnaire asking questions pertaining to route and source of agent,will only allow the agent to continue to spread, and should be regardedwith great suspicion!